PROJECT SUMMARY Infantile hemangiomas are the most common benign vascular tumor in infants, affecting 4-5% of children. Thirty percent of segmental infantile hemangiomas on the face and scalp are associated with birth defects of multiple organs. This condition is known as PHACE, an acronym for posterior fossa brain malformations, segmental facial hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal clefting. There is high morbidity associated with PHACE including risk to vision, congenital heart disease often requiring surgery, risk of stroke, deafness and neurodevelopmental delays. The hemangioma is a vascular tumor that requires treatment in infancy to prevent functional complications and disfigurement, but later undergoes involution. Our strategy is to use this highly valuable PHACE cohort to discover critical genes related to structural birth defects which will be a valuable resource to link multiple different projects in the Kids First Program. In Aim 1 we will analyze WGS to identify de novo genomic features in PHACE including single nucleotide variants, INDELS, copy number alterations, and structural variants. We then will use publicly available genome structural, epigenetic regulation, and gene expression data to identify epigenetic associations. In Aim 2 we will identify biologic processes affected by multiple different genomic variants for each major structural birth defect phenotype of PHACE. We will next use the Kids First Data Resource to integrate genomic and phenotypic data from a broad range of publicly available cohort databases to identify genetic pathways that are common to both PHACE and other childhood cancer and structural birth defect cohorts.